(4S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide (1.67 g, 10 mmol) was dissolved in DMF (17 ml). (S)-4-Chloromethyl-2,2-dimethyl-[1,3]dioxolane (1.52 g, 10 mmol) was added into the mixture. Finally Sodium tert-butoxide (0.98 g, 10 mmol) was added at room temperature. The mixture was heated to 100° C. with agitation for 23 hours under N2 atmosphere. UPLC indicated that there was 26% 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide remained in the mixture. Additional 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide (0.76 g, 5 mmol) and Sodium tert-butoxide (0.49 g, 5 mmol) was added. The mixture was stirred at 100° C. for another 24 hrs. HPLC indicated 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide was 9.4% remained, the selectivity of N1/N2 alkylation products was 2.8:1. The DMF was concentrated under reduced pressure. Water (10 ml) was added. The mixture was extracted with DCM (2×12 ml), the organic layer was washed with 10% aqueous NaCl (2×20 ml). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give oil, which is purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1) to give off-white solid (0.84 g), yield: 30%. 1H-NMR (400 MHz, d6-DMSO): δ 9.85 (s, 1H), 7.59 (s, 1H), 6.47 (s, 1H), 4.36-4.39 (m, 1H), 4.08-4.12 (m, 2H), 4.0-4.02 (m, 1H), 3.73-3.75 (m, 1H), 1.33 (s, 3H), 1.26 (s, 3H), 1.19 (s, 9H). The DMF was concentrated under reduced pressure Water (10 ml) was added The mixture was extracted with DCM (2×12 ml) the organic layer was washed with 10% aqueous NaCl (2×20 ml) The organic layer was dried over Na2SO4 concentrated under reduced pressure to give oil, which is purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide (1.67 g, 10 mmol) was dissolved in DMF (17 ml). (S)-4-Chloromethyl-2,2-dimethyl-[1,3]dioxolane (1.52 g, 10 mmol) was added into the mixture. Finally Sodium tert-butoxide (0.98 g, 10 mmol) was added at room temperature. The mixture was heated to 100° C. with agitation for 23 hours under N2 atmosphere. UPLC indicated that there was 26% 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide remained in the mixture. Additional 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide (0.76 g, 5 mmol) and Sodium tert-butoxide (0.49 g, 5 mmol) was added. The mixture was stirred at 100° C. for another 24 hrs. HPLC indicated 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide was 9.4% remained, the selectivity of N1/N2 alkylation products was 2.8:1. The DMF was concentrated under reduced pressure. Water (10 ml) was added. The mixture was extracted with DCM (2×12 ml), the organic layer was washed with 10% aqueous NaCl (2×20 ml). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give oil, which is purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1) to give off-white solid (0.84 g), yield: 30%. 1H-NMR (400 MHz, d6-DMSO): δ 9.85 (s, 1H), 7.59 (s, 1H), 6.47 (s, 1H), 4.36-4.39 (m, 1H), 4.08-4.12 (m, 2H), 4.0-4.02 (m, 1H), 3.73-3.75 (m, 1H), 1.33 (s, 3H), 1.26 (s, 3H), 1.19 (s, 9H). The DMF was concentrated under reduced pressure Water (10 ml) was added The mixture was extracted with DCM (2×12 ml) the organic layer was washed with 10% aqueous NaCl (2×20 ml) The organic layer was dried over Na2SO4 concentrated under reduced pressure to give oil, which is purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.15 g, 0.35 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.27 g, 1.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) was added N,N-dimethylformamide and the reaction mixture was heated to 100° C. overnight. The reaction was diluted with dichloromethane (20 mL) and washed with 1N hydrochloric acid (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and evaporated. The crude residue was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane) to yield the product (47 mg, 27%). ESI-MS m/z calc. 499.16. found 500.2 (M+1)+. Retention time 1.53 minutes. washed with 1N hydrochloric acid (10 mL) The organics were dried over sodium sulfate evaporated The crude residue was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.15 g, 0.35 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.27 g, 1.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) was added N,N-dimethylformamide and the reaction mixture was heated to 100° C. overnight. The reaction was diluted with dichloromethane (20 mL) and washed with 1N hydrochloric acid (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and evaporated. The crude residue was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane) to yield the product (47 mg, 27%). ESI-MS m/z calc. 499.16. found 500.2 (M+1)+. Retention time 1.53 minutes. washed with 1N hydrochloric acid (10 mL) The organics were dried over sodium sulfate evaporated The crude residue was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane)

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-nitrophenol 102 (2.00 g, 14.4 mmol), potassium carbonate (4.96 g, 35.9 mmol) and (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane 103 (2.55 mL, 18.7 mmol) in DMF (20 mL) was heated in a microwave reactor at 160° C. for 4 h. The crude reaction mixture was poured into H2O and extracted with dichloromethane (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by chromatography using ethyl acetate: pentane to obtain (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane 104 (1.90 g, 52% yield) as an amber-colored oil. The crude reaction mixture extracted with dichloromethane (3×15 mL) The combined organic layers were dried (Na2SO4) concentrated under reduced pressure The crude residue was purified by chromatography

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-nitrophenol 102 (2.00 g, 14.4 mmol), potassium carbonate (4.96 g, 35.9 mmol) and (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane 103 (2.55 mL, 18.7 mmol) in DMF (20 mL) was heated in a microwave reactor at 160° C. for 4 h. The crude reaction mixture was poured into H2O and extracted with dichloromethane (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by chromatography using ethyl acetate: pentane to obtain (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane 104 (1.90 g, 52% yield) as an amber-colored oil. The crude reaction mixture extracted with dichloromethane (3×15 mL) The combined organic layers were dried (Na2SO4) concentrated under reduced pressure The crude residue was purified by chromatography

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of methyl 3-hydroxybenzoate (10.0 g, 65.8 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (13.0 g, 98.7 mmol) and K2CO3 (18.0 g, 132 mmol) in DMF (100 ml) was stirred for 18 h at 160° C. The mixture was diluted with water (150 mL) and adjusted to pH=6 by the addition of 3N HCl. The mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% Ethyl acetate in petroleum ether) to give (R)-methyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate as a brown oil, (8.5 g, 49% yield). The mixture was extracted with ethyl acetate (200 ml×3) the combined organic layers were dried (MgSO4) concentrated under reduced pressure The residue was purified by column chromatography (10% Ethyl acetate in petroleum ether)

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of methyl 3-hydroxybenzoate (10.0 g, 65.8 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (13.0 g, 98.7 mmol) and K2CO3 (18.0 g, 132 mmol) in DMF (100 ml) was stirred for 18 h at 160° C. The mixture was diluted with water (150 mL) and adjusted to pH=6 by the addition of 3N HCl. The mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% Ethyl acetate in petroleum ether) to give (R)-methyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate as a brown oil, (8.5 g, 49% yield). The mixture was extracted with ethyl acetate (200 ml×3) the combined organic layers were dried (MgSO4) concentrated under reduced pressure The residue was purified by column chromatography (10% Ethyl acetate in petroleum ether)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared according to the procedure used for Example 9 synthesis by reaction of (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane with compound 9F, followed by hydrolysis with 1N HCl. 1H NMR (400 MHz, MeOD) δ ppm 1.71 (s, 3 H) 3.44-3.51 (m, 1 H) 3.59 (d, J=5.31 Hz, 2 H) 3.74 (s, 3 H) 3.76-3.82 (m, 1 H) 3.91-4.01 (m, 1 H) 4.41 (dd, J=13.64, 3.28 Hz, 1 H) 6.77 (t, J=8.59 Hz, 1 H) 7.26 (d, J=9.09 Hz, 1 H) 7.39 (d, J=2.02 Hz, 1 H) 8.38 (s, 1 H)) [M+H] calc'd for C18H18BrFN4O4, 454; found, 454.

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5-Chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (8.3 g, 36.8 mmol, 1 eq, compound 8D), cesium carbonate (47.9 g, 147.5 mmol, 4e q) and potassium iodide (30 mg, cat) were stirred in anhydrous DMF (180 mL, 0.4 M) containing 4 Å molecular sieves (2.49 g) under N2. After 15 minutes (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (25.1 mL, 184 mmol, 5 eq) was added and the mixture stirred at 120° C. for 12 hours. DCM (150 mL) was added and the organic layer washed with water (150 mL) dried over magnesium sulfate and evaporated. The residue was purified by silica chromatography using 0-70% EtOAc/Hexane as eluent to give 4.8 g of product. [M+H] calc'd for C15H18ClN3O4, 340; found, 340. containing 4 Å molecular sieves (2.49 g) under N2 the organic layer washed with water (150 mL) dried over magnesium sulfate evaporated The residue was purified by silica chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared according to the procedure used for Example 9 synthesis by reaction of (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane with compound 9F, followed by hydrolysis with 1N HCl. 1H NMR (400 MHz, MeOD) δ ppm 1.71 (s, 3H) 3.44-3.51 (m, 1H) 3.59 (d, J=5.31 Hz, 2H) 3.74 (s, 3H) 3.76-3.82 (m, 1H) 3.91-4.01 (m, 1H) 4.41 (dd, J=13.64, 3.28 Hz, 1H) 6.77 (t, J=8.59 Hz, 1H) 7.26 (d, J=9.09 Hz, 1H) 7.39 (d, J=2.02 Hz, 1H) 8.38 (s, 1H)) [M+H] calc'd for C18H18BrFN4O4, 454; found, 454.

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5-Chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (8.3 g, 36.8 mmol, 1 eq, compound 8D), cesium carbonate (47.9 g, 147.5 mmol, 4 eq) and potassium iodide (30 mg, cat) were stirred in anhydrous DMF (180 mL, 0.4 M) containing 4 Å molecular sieves (2.49 g) under N2. After 15 minutes (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (25.1 mL, 184 mmol, 5 eq) was added and the mixture stirred at 120° C. for 12 hours. DCM (150 mL) was added and the organic layer washed with water (150 mL) dried over magnesium sulfate and evaporated. The residue was purified by silica chromatography using 0-70% EtOAc/Hexane as eluent to give 4.8 g of product. [M+H] calc'd for C15H18ClN3O4, 340; found, 340. containing 4 Å molecular sieves (2.49 g) under N2 the organic layer washed with water (150 mL) dried over magnesium sulfate evaporated The residue was purified by silica chromatography